|Publication number||US5152986 A|
|Application number||US 07/426,123|
|Publication date||Oct 6, 1992|
|Filing date||Oct 24, 1989|
|Priority date||Jun 13, 1987|
|Also published as||CA1318078C, CN1054040C, CN1081951C, CN1108968A, CN88103473A, DE3719764A1, EP0295495A1, EP0295495B1|
|Publication number||07426123, 426123, US 5152986 A, US 5152986A, US-A-5152986, US5152986 A, US5152986A|
|Inventors||Peter M. Lange, Alfred Mitschker, Arundev H. Naik, Hubert Rast, Martin Scheer, Herbert Voege|
|Original Assignee||Bayer Aktiengesellschaft|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (7), Referenced by (31), Classifications (24), Legal Events (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application is a continuation-in-part of application Ser. No. 203,354, filed Jun. 6, 1988, now abandoned.
The present invention relates to ion exchange resins which are loaded with quinolonecarboxylic acid derivatives, processes for their preparation and their use.
It has long been known to bind pharmaceutically active compounds to ion exchange resins in order, for example, to make active compounds having a pronounced inherent odor more utilizable (Swiss Patent Specification 383,552). It is also known to bind pharmaceutically active compounds to ion exchange resins in order to effect uniform release of the active compound over a longer period of time (EP-OS (European Published Specification) 42,818).
It is furthermore known to bind anthelmintic active compounds to ion exchange resins in order to influence the flavor of the active compounds (DE-OS (German Published Specification) 3,028,082).
Quinolonecarboxylic acids, and their derivatives, bound to ion exchange resins as described hereinbelow were hitherto unknown.
The present invention relates to:
1. Weak cation exchange resins which are loaded with quinolonecarboxylic acid derivatives of the formula (I) ##STR1## in which R1 represents methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl,
R2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,
R3 represents methyl or a cyclic amino group such as ##STR2## wherein R4 represents hydrogen, alkyl having 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, formyl, CFCl2 -SO, CFCl2 -SO2 -, CH3 O-CO-S-, benzyl, 4-aminobenzyl or the radical ##STR3## R5 represents hydrogen or methyl, R6 represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyloxymethyl,
R7 represents hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxyl or hydroxymethyl,
R8 represents hydrogen, methyl, ethyl or chlorine,
X represents fluorine, chlorine or nitro and
A represents N or C-R9, wherein
R9 represents hydrogen, halogen such as fluorine or chlorine, methyl or nitro or alternatively, together with R1, can form a bridge of the structure ##STR4## 2. Process for the preparation of ion exchange resins which are loaded with quinolonecarboxylic acid derivatives of the formula (I) by treating ion exchange resins with solutions or suspensions of quinolonecarboxylic acid derivatives of the formula (I) in water or in polar solvents.
3. Use of ion exchange resins which are loaded with quinolonecarboxylic acid derivatives of the formula (I), to improve the flavor and also to delay the release of the quinolonecarboxylic acid derivatives of the formula (I),
4. Medicaments, including feed medicaments, which contain ion exchange resins which are loaded with quinolonecarboxylic acid derivatives of the formula (I).
5. Solid, orally administered medicaments and also feedstuffs which contain ion exchangers which are loaded with quinolonecarboxylic acid derivatives of the formula (I).
Suitable weak cation exchange resins can have a matrix which is gelatinous or macroporous. Possible base monomers for the ion exchange polymerizable monomers which can be converted into cation exchanger resins by suitable functionalization. Monomers which may be mentioned are, for example, (meth)acrylates, (meth)acrylonitrile and also styrene derivatives. Polyvinyl compounds, such as, for example, divinylbenzene, ethylene glycol dimethacrylate or methylene bisacrylamide are employed as further comonomers for the preparation of the base polymers. Condensation resins, which lead to cation exchangers, such as, for example, the resins resulting from the reaction of phenol and formaldehyde with polyamines, are also suitable as carriers for the quinolonecarboxylic acid derivatives of the formula (I).
The utilizable ion exchangers are not new. The preparation of these resins is described, for example, in Ullmanns Enzyklopadie der techn. Chemie (Ullmann's Encyclopaedia of Industrial Chemistry) Vol. 13, 4th edition, pages 279 to 307, especially pages 299 to 305 and particularly page 301. The preferred macroporous resins can exhibit variable pore volumes. The degree of cross-linking of the suitable ion exchange resins should preferably be up to 20% and particularly preferably up to 12l%. The synthetic resins are present in particle sizes from 50 to 1300 μm, preferably from 100 to 300 μm.
The use of ground ion exchangers may be mentioned in particular. In this case, the grinding can occur before or after the loading with the quinolonecarboxylic acids of the formula (I).
Particularly suitable as the weak cation exchange resin are carboxyl containing resins, especially such as those identified as Lewatit CNP, viz. Lewatit CNP/80, CNP/80-BG, CNP/80-ST, CNP/80-WS and CNP LF.
Such resins are particularly suited since they bind the active compound of the animal medication strongly enough to mask its bitter taste, i.e. dissociation in the mouth and on the tongue of the animal is low enough to mask the bitter taste. Otherwise the animal would not take up enough medicament. However, once the salt formed by the cation exchanger and the active compound has passed the taste region and comes down the gut into the digestive tract it has to dissociate. Good dissociation in the digestive tract is essential in order to ensure blood levels of the active compound high enough to be effective. These demands are in conflict with each other. These demands are also different from the classical slow release formulations for which ion-exchange salts have been used hitherto and wherein the only condition the slow release formulation has to fulfill is that the active material is freed over a period of time.
It has been shown, and is exemplified hereinbelow, that strong cation exchange resins form salts which do not dissociate in water and therefore will not taste bad. However, the strong resinous salts do not free enough active amount in the digestive tract. Surprisingly, salts of weak cation exchangers do not dissociate in water, and therefore also do not taste bad. However, in contrast to the other salts, in the digestive tract they set free their load of active compound, thus guaranteeing sufficient blood levels.
The quinolonecarboxylic acids of the formula (I) and their preparation have been disclosed (DE-OS (German Published Specification) 3,033,157).
Preferred active compounds are quinolonecarboxylic acids of the formula (II) ##STR5## in which R3 represents ##STR6## A, R4, R5 and R6 have the abovementioned meaning.
Particularly preferred active compounds are quinolonecarboxylic acids of the formula (II), in which R3 represents ##STR7## R4 represents hydrogen, methyl or ethyl, R5 represents hydrogen or methyl, especially hydrogen,
R6 represents hydrogen or methyl, especially hydrogen, and
A has the abovementioned meaning.
The following quinolonecarboxylic acids and their derivatives may be mentioned in particular as active compounds: 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl or 4-methyl- or 4-ethyl-1-piperazinyl)-quinolone-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinolone-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinolone-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7,4-pyrido[1,2,4-de]1,4-benzoxazine-6-carboxylic acid,. and also the methyl and ethyl esters of these compounds. Ciprofloxacin and enrofloxacin may be mentioned as being especially preferred.
The degree of loading of the ion exchange resins with the quinolonecarboxylic acid derivatives is between 10 and 150% by weight of the dried ion exchanger, depending on the type of resin.
Release experiments show that the active compound is particularly well released in liquids with pH's from 1 to 3.
The preparation of the ion exchange resins which are loaded with quinolonecarboxylic acid derivatives of the formula (I) takes place in water or polar organic solvents, such as, for example, alcohols such as methanol or ethanol, ketones such as acetone or mixtures thereof. Water is particularly preferred. Ion exchanger and active compound are in this case stirred in water at room temperature (for example 5 to 24 hours) until the active compound is completely bound.
As already mentioned, the ion exchangers loaded with quinolonecarboxylic acid derivatives of the formula (I) can be used for the preparation of medicaments. As such, medicaments for animals may be mentioned in particular.
Medicament preparations suitable for animals are, for example, those in which improvement of flavor plays a role in intake or in which a delayed release of active compound after administration is sought.
These are, for example, solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boli and capsules; or suspensions which are administered orally or cutaneously, for example. They are prepared by suspending the resin loaded with active compound in an excipient liquid, where appropriate with the addition of further auxiliaries such as wetting agents, colorants, absorption promotors, preservatives, antioxidants and light screens.
By adding substances which increase the viscosity, these suspensions can also be administered as so-called "semi-solid" preparations such as, for example, ointments. In particular, formulations of this type are employed for the treatment of udder disorders (mastitis) or as oral pastes for cats, dogs and horses.
For the preparation of solid preparations, the resin loaded with active compound is mixed with suitable excipients, where appropriate with the addition of auxiliaries, and brought into the desired form.
Excipients which may be mentioned are all physiologically acceptable solid inert substances. Inorganic and organic substances serve as such. Inorganic substances are, for example, common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, aluminas, precipitated or colloidal silicon dioxide and phosphates.
Organic substances are, for example, sugar, cellulose, food-stuffs and feedstuffs such as powdered milk, animal meals, ground cereal meals and crushed cereal meals and starches.
Auxiliaries are preservatives, antioxidants and colorants, which have already been mentioned above.
Further suitable auxiliaries are lubricants and glidants, such as, for example, magnesium stearate, stearic acid, talc, bentonites, disintegration-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binding agents, such as, for example, starch, gelatin or linear polyvinylpyrrolidone and also dry binding agents such as microcrystalline cellulose.
For the preparation of suspensions, the resins loaded with active compound are distributed as homogeneously as possible in an excipient medium, where appropriate with the assistance of other auxiliaries such as wetting agents, preservatives or viscosity-increasing substances.
Excipient liquids which may be mentioned are all homogeneous solvents and solvent mixtures, but in particular water.
Wetting agents (dispersing agents) which may be mentioned are:
1. anion-active surfactants including emulsifiers such as Na lauryl sulphate, fatty alcohol ether sulphates, mono/dialkyl polyglycol ether orthophosphate monoethanolamine salt, ligninsulphonates or dioctyl sulphosuccinate,
2. cation-active surfactants, including emulsifiers, such as cetyltrimethylammonium chloride,
3. ampholytic surfactants, including emulsifiers, such as di-Na N-lauryl-β-iminodipropionate or lecithin,
4. non-ionogenic surfactants, including emulsifiers, such as polyoxyethylated castor oil, polyoxyethylated sorbitan monoleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers and PluronicŪ.
The non-ionic surfactants are particularly preferred.
Further auxiliaries are, for example: Colorants, i.e. all colorants permitted for administration to animals, which can be dissolved or suspended.
Antioxidants such as, for example, sulphites or metabisulphites, such as potassium metabisulphite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole and tocopherol.
Thickeners or viscosity-increasing substances such as, for example, inorganic thickeners such as bentonites, colloidal silica and aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates, alginates, gelatin, polyvinyl pyrrolidone, polyethylene glycols, waxes, gum arabic and xanthan gum or mixtures of the abovementioned substances.
The ion exchange resins loaded with active compound can be added to the feed as such or in the form of premixes or feed concentrates.
Premixes and feed concentrates are mixtures of the active compound with a suitable excipient.
The single feedstuffs or mixtures thereof, and also the abovementioned inert excipients, count as excipients.
Moreover, they can contain further auxiliaries, such as, for example, substances which regulate the flow capability and miscibility, such as, for example, silicas, bentonites and ligninsulphonates. Moreover, antioxidants such as BHT or preservatives such as sorbic acid or calcium propionate can be added. In addition, for powder-binding, liquids such as paraffin oils, vegetable oils and propylene glycols can be admixed to the premixes.
The resins loaded with active compound can be present in the formulations alone or mixed with other active compounds, mineral salts, trace elements, vitamins, proteins, colorants, fats or flavorings.
Other active compounds can be, for example, penicillins, their salts and derivatives, such as, for example, the procaine salt of penicillin G, or derivatives thereof such as oxacillin or cloxacillin.
The administration of the ion exchange resins loaded with active compound preferably takes place together with the feed.
Single feedstuffs of vegetable origin such as hay, beets, cereals, cereal by-products, single feedstuffs of animal origin such as meat, fats, milk products, bonemeal, fish products, and furthermore single feedstuffs such as vitamins, proteins, amino acids, for example DL-methionine, salts such as calcium carbonate and common salt count as feed. Supplementary feedstuffs, finished feedstuffs and mixed feedstuffs also count as feed. These containing single feedstuffs in a composition which guarantees balanced nutrition with respect to the energy and protein supply and also the supply of vitamins, mineral salts and trace elements.
The concentration of the ion exchangers in the feed is normally about 0.01-500 ppm, preferably 10-200 pm.
100 ml of a suspension of 5 g of enrofloxacin in demineralized water are stirred with 35 ml of Lewatitφ S 100 H+ form until the clearing of the aqueous phase. This process was then repeated until no clear aqueous phase can be obtained, even after stirring for 24 hours. After separation of the resin, the amount of enrofloxacin taken up is determined by differential weighing of the dried resin before and after loading. 7.7 g of enrofloxacin are bound in this experiment.
2714 ml of LewatitŪ SPC 108 H+ -form are stirred overnight together with 5000 ml of demineralized water and 782 g of enrofloxacin. The resin is isolated from the clear aqueous phase and washed twice with one bed volume of water each time. After drying for 48 hours at 60° C. in a vacuum drying cabinet, 1496 g of the preparation according to the invention are thus obtained.
80 ml of LewatitŪ CNP H+ -form are stirred at room temperature together with 500 ml of demineralized water and 8 g of enrofloxacin. After stirring for 3 hours, the aqueous phase is clear. The ion exchanger has bound the entire active compound.
______________________________________Enrofloxacin-ion exchanger according 4.85 kgto Example 2(4.85 g correspond to 2.5 g ofenrofloxacin)Wheat flour 95.15 kg 100.00 kg______________________________________
The substances are homogeneously mixed in a mixer.
______________________________________(9.7 g correspond to 5.0 g of 9.7 kgenrofloxacin)vegetable oil 4.0 kglimestone meal 86.3 kg 100.0 kg______________________________________
The lime meal is premixed with the vegetable oil and the active compound resin is homogeneously distributed therein.
______________________________________Enrofloxacin-ion exchanger according to 1.88 kgExample 2(1.88 g correspond to 1 g ofenrofloxacin)particle size - mean value 0.1 mmglycerol 10.00 gbenzyl alcohol 1.00 gflavoring 0.20 gMethylhydroxypropyl cellulose gel 2% to 100 ml______________________________________
A 2% strength methylhydroxypropyl cellulose gel is prepared in a customary manner. Benzyl alcohol and flavoring are dissolved and the active compound according to the invention is suspended therein.
______________________________________1. Enrofloxacin-ion exchanger according to 18.8 g Example 2 (18.8 g correspond to 10.0 g of enrofloxacin)2. Lactose 50.0 g3. Corn starch 29.2 g4. Gelatin 2.0 g 100.0 g______________________________________
The substances 1, 2 and 3 are mixed. A gelatin solution is prepared from 4 using 22.0 g of water. The mixture is kneaded with it. The solid dough is comminuted through a grater and dried and then sieved to the desired particle size.
______________________________________Enrofloxacin-ion exchanger according to 12.5 kgExample 2Limestone meal 86.0 kgPolyoxyethylated castor oil 1.5 kg 100.0 kg______________________________________
Limestone meal is mixed together with polyoxyethylated castor oil until homogeneous. The active compound is then added and mixed to homogenity.
Piglets having a mean weight of 14.8 kg each received twice daily 0.3 kg of feed for rearing piglets which was mixed with the indicated amount of enrofloxacin. In each case, blood was taken 1 hour after feeding and the content of active compound in the serum determined. The following values were established:
______________________________________ Level of active compound μg/mlContent of active 1 hr. after 1st 1 hr. after 2ndcompound ppm feeding feeding______________________________________100 0.3 0.5200 0.6 0.6400 1.1 1.0______________________________________
Piglets with a mean weight of 14.8 kg received, twice daily, 0.3 kg of feed for rearing piglets to which was added the pure active compound enrofloxacin, and ion exchange resin which was loaded with active compound. The residual feed in the trough was determined after the given times. The following results were established in this way:
______________________________________Content of active Residual feedcompound Number of in % afterppm animals 15 30 60 min______________________________________0 9 5 0 0400 (pure 12 80 70 70active compound)400 (active 11 10 0 0compound bound toion exchanger)______________________________________
The following ion exchangers loaded with Enrofloxacin were prepared:
1. Ion exchanger with --SO3 - H+ binding groups: 2714 ml of LewatitŪ SPC 108 H+ form were stirred overnight together with 5000 ml of demineralized water and 782 g of Enrofloxacin. The resin was isolated from the clear aqueous phase and washed twice with one bed volume of water each time. After drying for 48 hours at 60° C. in a vacuum drying cabinet, 1496 g of the preparation were obtained. The dry ion exchanger has a 38% content of Enrofloxacin.
2. Ion exchanger with --COO-- H+ binding groups: 80 ml of LewatitŪ CNP H+ -form were stirred at 60° C. together with 500 ml of demineralized water and 8 g of Enrofloxacin. After stirring for 3 hours, the aqueous phase was clear. The ion exchanger bound all the active compound. The dry ion exchanger had a 30.5% content of Enrofloxacin.
Samples of the loaded ion-exchangers prepared according to these 1 and 2 were used in the following trials:
A Trial simulating taste (From former experiments it is known that in order to avoid refusal of an edible formulation containing Enrofloxacin by pigs due to the bitter taste of the formulations the content of free Enrofloxacin has to be below 10 ppm.)
A1 2.63 g of the loaded ion exchanger of 1 was stirred at room temperature in 1 liter of demineralized water. After 1 hour the water overlay was analyzed and a content of <10 ppm Enrofloxacin was found.
A2 3.27 g of the loaded ion exchanger of 2 was stirred at room temperature in 1 liter of demineralized water. After 1 hour the water overlay was analyzed and a content of <10 ppm Enrofloxacin has been determined.
The results show that both ion-exchange resins bind Enrofloxacin sufficiently strongly to avoid bad taste in edible formulations.
B1 2.63 g of the loaded ion exchanger of 1 was stirred at room temperature in 1 liter of 0.1N HCl. After 72 hours only 20-30% of the Enrofloxacin was freed.
B2 3.27 g of the loaded ion exchanger of 2 was stirred at room temperature in 1 liter of 0.1N HCl. After 24 hours 100% of the bound Enrofloxacin was freed.
This shows that only the weak cation-exchange resin freed the active compound sufficiently to enable its therapeutic use.
It will be appreciated that the instant specification and claims are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3051623 *||Apr 24, 1959||Aug 28, 1962||Wallace & Tiernan Inc||Codeine and 2-methyl-3-o-tolyl-4-quin-azolone analgesic composition|
|US3317388 *||Nov 20, 1964||May 2, 1967||Wallace & Tiernan Inc||Methods for treating pain|
|US4762709 *||Jan 31, 1986||Aug 9, 1988||Pennwalt Corporation||Liquid prolonged release pharmaceutical formulations containing ionic constituents|
|US4826982 *||Sep 2, 1986||May 2, 1989||Kyorin Pharmaceutical Co., Ltd.||Quinolonecarboxylic acid derivatives|
|US4871832 *||Jan 21, 1988||Oct 3, 1989||Sumitomo Chemical Company, Ltd.||Thermosettable imide compound and epoxy resin composition containing the same|
|US4874764 *||Jun 18, 1987||Oct 17, 1989||Otsuka Pharmaceutical Company, Limited||Benzoheterocyclic compounds|
|US4980353 *||May 13, 1986||Dec 25, 1990||Bayer Aktiengesellschaft||1-aryl-4-quinolone-3-carboxylic acids|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US5980882 *||Apr 16, 1997||Nov 9, 1999||Medeva Pharmaceuticals Manufacturing||Drug-resin complexes stabilized by chelating agents|
|US6261601||Sep 14, 1998||Jul 17, 2001||Ranbaxy Laboratories Limited||Orally administered controlled drug delivery system providing temporal and spatial control|
|US6514492 *||Jul 12, 2000||Feb 4, 2003||Schering-Plough Veterinary Corporation||Taste masking of oral quinolone liquid preparations using ion exchange resins|
|US6716448||Oct 5, 2001||Apr 6, 2004||Rubicon Scientific Llc||Domesticated household pet food including maintenance amounts of ivermectin|
|US6866862||Oct 5, 2001||Mar 15, 2005||Rubicon Scientific||Animal feeds including heartworm-prevention drugs|
|US7052712||Oct 5, 2001||May 30, 2006||Rubicon Scientific Llc||Animal feeds including actives and methods of preparing same|
|US7112336||Apr 30, 2004||Sep 26, 2006||Bayer Healthcare Llc||Solid phase dispersion of quinolone or naphthyridonecarboxylic acids|
|US7175856 *||Mar 11, 2003||Feb 13, 2007||Bristol-Myers Squibb Company||Palatable oral suspension and method|
|US7514451||Sep 8, 2004||Apr 7, 2009||Kyorin Pharmaceutical Co., Ltd.||7-(4-Substituted-3-cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative|
|US7858120 *||Oct 30, 2004||Dec 28, 2010||Bayer Animal Health Gmbh||Pharmaceutical formulations containing flavouring substances with improved pharmaceutical properties|
|US8106072||Feb 26, 2009||Jan 31, 2012||Kyorin Pharmaceutical Co., Ltd.||7- (4-substituted-3-cyclopropylaminomethyl-1-pyrrolidinyl) quinolonecarboxylic acid derivative|
|US8222407||May 23, 2008||Jul 17, 2012||Kyorin Pharmaceutical Co., Ltd.||Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position|
|US8545829 *||May 19, 2003||Oct 1, 2013||Bayer Intellectual Property Gmbh||Pharmaceutical preparations for oral administration, containing ion-exchange resins loaded with active ingredients and intrinsically viscous gelling agents as thickening agents|
|US9138739 *||Dec 27, 2011||Sep 22, 2015||Dow Global Technologies Llc||Method for inhibiting nitrosamine formation in anion exchange resins|
|US20030187019 *||Mar 11, 2003||Oct 2, 2003||Ismat Ullah||Palatable oral suspension and method|
|US20040247560 *||Jul 4, 2002||Dec 9, 2004||Martin Dirk||Pharmaceutical preparations comprising iox exchange resins charged with active ingrdients|
|US20060177414 *||May 19, 2003||Aug 10, 2006||Dirk Mertin||Pharmaceutical preparations for oral adminstration, containing ion-exchange resins loaded with active ingredients and intrinsically viscous gelling agents as thickening agents|
|US20060281779 *||Sep 8, 2004||Dec 14, 2006||Kyorin Pharmaceutical Co., Ltd.||7-(4-Substituted-3-cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative|
|US20070036843 *||Jan 27, 2006||Feb 15, 2007||Collegium Pharmaceutical, Inc.||Non-ionic non-aqueous vehicles for topical and oral administration of carrier-complexed active agents|
|US20070196466 *||Oct 30, 2004||Aug 23, 2007||Patrick Bosche||Pharmaceutical formulations containing flavouring substances with improved pharmaceutical properties|
|US20090028936 *||Jun 14, 2004||Jan 29, 2009||Bayer Healthcare Ag||Tablets containing enrofloxacin and flavouring agents and/or flavours|
|US20110065719 *||Nov 19, 2010||Mar 17, 2011||Bayer Animal Health Gmbh||Pharmaceutical formulations containing flavouring substances with improved pharmaceutical|
|US20120172463 *||Dec 27, 2011||Jul 5, 2012||Chris Raymond Eicher||Method for inhibiting nitrosamine formation in anion exchange resins|
|US20120172464 *||Jul 5, 2012||Chris Raymond Eicher||Method for inhibiting nitrosamine formation in anion exchange resins|
|US20120172465 *||Jul 5, 2012||Chris Raymond Eicher||Anion exchange resins having controlled nitrosamine formation|
|WO1998007428A1 *||Aug 7, 1997||Feb 26, 1998||Bayer Ag||Orally applicable formulation of quinolone or naphthyridone carboxylic acids|
|WO2000025765A2 *||Oct 19, 1999||May 11, 2000||Bayer Ag||Aqueous drug formulation for oral application|
|WO2001005431A1 *||Jul 12, 2000||Jan 25, 2001||Fan Allan Chor Lun||Taste masking of oral quinolone liquid preparations using ion exchange resins|
|WO2003007995A2 *||Jul 4, 2002||Jan 30, 2003||Bayer Ag||Pharmaceutical preparations containing ion exchange resins charged with fluoroquinolone|
|WO2005000275A1 *||Jun 14, 2004||Jan 6, 2005||Bayer Healthcare Ag||Tablets containing enrofloxacin and flavouring agents and/or flavours|
|WO2006081518A2 *||Jan 27, 2006||Aug 3, 2006||Collegium Pharmaceutical Inc||Non-ionic non-aqueous vehicles for topical and oral administration of carrier-complexed active agents|
|U.S. Classification||424/78.14, 424/442, 424/78.15|
|International Classification||A23K1/00, A61K47/30, A61K31/535, B01J39/18, B01J41/12, A61K9/18, A61K31/44, A61K31/47, C08J5/20, A61K31/495, A61K9/00, A61K47/48, A23K1/16|
|Cooperative Classification||A61K47/48184, A61K31/44, A61K31/47, A61K31/535|
|European Classification||A61K31/47, A61K47/48K4D, A61K31/535, A61K31/44|
|Oct 24, 1989||AS||Assignment|
Owner name: BAYER AKTIENGESELLSCHAFT BAYERWERK, A GERMAN CORP.
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:LANGE, PETER M.;MITSCHKER, ALFRED;NAIK, ARUNDEV H.;AND OTHERS;REEL/FRAME:005167/0603
Effective date: 19891012
|Mar 14, 1996||FPAY||Fee payment|
Year of fee payment: 4
|Mar 20, 2000||FPAY||Fee payment|
Year of fee payment: 8
|Mar 8, 2004||FPAY||Fee payment|
Year of fee payment: 12
|Feb 5, 2009||AS||Assignment|
Owner name: BAYER ANIMAL HEALTH GMBH, GERMANY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BAYER AKTIENGESELLSCHAFT;REEL/FRAME:022203/0772
Effective date: 20081204